14-23416185-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM5 PP2 BP4_Moderate

The NM_000257.4(MYH7):c.4772T>A(p.Leu1591Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1591P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 1.37

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

MHRT (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000257.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23416185-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190406.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, MYH7
• BP4: Computational evidence support a benign effect (MetaRNN=0.11719307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.4772T>A	p.Leu1591Gln	missense_variant	34/40	ENST00000355349.4
MHRT	NR_126491.1	n.446A>T		non_coding_transcript_exon_variant	3/6
MYH7	NM_001407004.1	c.4772T>A	p.Leu1591Gln	missense_variant	33/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.4772T>A	p.Leu1591Gln	missense_variant	34/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251476 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135910

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461846 Hom.: 0 Cov.: 34 AF XY: 0.0000344 AC XY: 25 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152088 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74280

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces leucine with glutamine at codon 1591 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden cardiac death and myocarditis (PMID 25447171). This individual and six relatives diagnosed with arrhythmogenic cardiomyopathy all carried a pathogenic truncation variant in the PKP2 gene that could explain the observed phenotype in this family (PMID: 31156706). This variant has been identified in 10/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 21, 2022	This missense variant replaces leucine with glutamine at codon 1591 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden cardiac death and myocarditis (PMID 25447171). This individual and six relatives diagnosed with arrhythmogenic cardiomyopathy all carried a pathogenic truncation variant in the PKP2 gene that could explain the observed phenotype in this family (PMID: 31156706). This variant has been identified in 10/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 21, 2020	- -

Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 01, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 07, 2022

- -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 12, 2022

This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 1591 of the MYH7 protein (p.Leu1591Gln). This variant is present in population databases (rs730880808, gnomAD 0.007%). This missense change has been observed in individual(s) with Laing distal myopathy (PMID: 22918376). ClinVar contains an entry for this variant (Variation ID: 181265). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH7 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2021

The p.L1591Q variant (also known as c.4772T>A), located in coding exon 32 of the MYH7 gene, results from a T to A substitution at nucleotide position 4772. The leucine at codon 1591 is replaced by glutamine, an amino acid with dissimilar properties. This alteration has been reported in at least two cases of sudden cardiac death and has been seen in at least one hypertrophic cardiomyopathy (HCM) cohort (Campuzano O et al. Front Genet, 2019 May; Yamaguchi-Kabata Y et al. J Hum Genet, 2018 Feb;63:213-230; 10:450; Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Campuzano O et al. J. Am. Coll. Cardiol., 2015 Dec;66:2913-2914; Campuzano O et al. Forensic Sci Int, 2014 12;245:30-7). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostCm	Benign	0.056
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	16
Dann	Benign	0.93
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-1.8	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.25
Sift	Benign	1.0	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.23
MVP		0.62
MPC		0.64
ClinPred		0.030	T
GERP RS		4.5
Varity_R		0.22
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs730880808; hg19: chr14-23885394; COSMIC: COSV62524609; COSMIC: COSV62524609;